title: Adsorption of α-synuclein to supported lipid bilayers: positioning and role of electrostatics.
abstract: An amyloid form of the protein α-synuclein is the major component of the intraneuronal inclusions called Lewy bodies, which are the neuropathological hallmark of Parkinson's disease (PD). α-Synuclein is known to associate with anionic lipid membranes, and interactions between aggregating α-synuclein and cellular membranes are thought to be important for PD pathology. We have studied the molecular determinants for adsorption of monomeric α-synuclein to planar model lipid membranes composed of zwitterionic phosphatidylcholine alone or in a mixture with anionic phosphatidylserine (relevant for plasma membranes) or anionic cardiolipin (relevant for mitochondrial membranes). We studied the adsorption of the protein to supported bilayers, the position of the protein within and outside the bilayer, and structural changes in the model membranes using two complementary techniques-quartz crystal microbalance with dissipation monitoring, and neutron reflectometry. We found that the interaction and adsorbed conformation depend on membrane charge, protein charge, and electrostatic screening. The results imply that α-synuclein adsorbs in the headgroup region of anionic lipid bilayers with extensions into the bulk but does not penetrate deeply into or across the hydrophobic acyl chain region. The adsorption to anionic bilayers leads to a small perturbation of the acyl chain packing that is independent of anionic headgroup identity. We also explored the effect of changing the area per headgroup in the lipid bilayer by comparing model systems with different degrees of acyl chain saturation. An increase in area per lipid headgroup leads to an increase in the level of α-synuclein adsorption with a reduced water content in the acyl chain layer. In conclusion, the association of α-synuclein to membranes and its adsorbed conformation are of electrostatic origin, combined with van der Waals interactions, but with a very weak correlation to the molecular structure of the anionic lipid headgroup. The perturbation of the acyl chain packing upon monomeric protein adsorption favors association with unsaturated phospholipids preferentially found in the neuronal membrane.
authors.affiliation: Biophysical Chemistry, Department of Chemistry, Lund University , SE-22100 Lund, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Hellstrand
authors.forename: Marie
authors.initials: M
authors.lastname: Grey
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Ainalem
authors.forename: John
authors.initials: J
authors.lastname: Ankner
authors.forename: V Trevor
authors.initials: VT
authors.lastname: Forsyth
authors.forename: Giovanna
authors.initials: G
authors.lastname: Fragneto
authors.forename: Michael
authors.initials: M
authors.lastname: Haertlein
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Dauvergne
authors.forename: Hanna
authors.initials: H
authors.lastname: Nilsson
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.forename: Sara
authors.initials: S
authors.lastname: Linse
authors.forename: Tommy
authors.initials: T
authors.lastname: Nylander
authors.forename: Emma
authors.initials: E
authors.lastname: Sparr
mesh_terms: D000327:Adsorption; D000686:Amyloidosis / Q000473:pathology / Q000503:physiopathology; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D016631:Lewy Bodies / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D033363:Neutron Diffraction; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D055672:Static Electricity; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology
chemical_list: D008051:Lipid Bilayers; D008563:Membrane Lipids; D010743:Phospholipids; C497604:SNCA protein, human; D051844:alpha-Synuclein